Despite advances in antibiotic therapy and cardiopulmonary support, septic shock remains a highly lethal disease. Sepsis is the leading cause of death in trauma and immunosuppressed patients hospitalized in intensive care units. Cellular mediators such as the neutrophil may play paradoxical roles in this process. While it is clear that the neutrophil is important in host defense, in vitro and in vivo studies suggest that the neutrophil, under the influence of other activated endogenous mediators, has the potential to contribute to tissue injury during sepsis. Recombinant colony stimulating factors such as granulocyte (rG-CSF) and granulocyte-macrophage colony stimulating factor (rG-CSF) are capable of both increasing bone marrow leukocyte production as well as increasing the activity level of circulating and resident tissue cells. Administration of these factors improves survival in irradiated neutropenic animal models and decreases the frequency of infection in neutropenic patients. The use of such factors in non-neutropenic patients with sepsis has the potential to be either harmful or beneficial. We have shown that rG-CSF pretreatment in a non-neutropenic canine model of lethal bacterial peritonitis improves cardiovascular function and survival. These improvements are associated with decreases in circulating endotoxin levels. Although rG-CSF accelerates alveolar neutrophil recruitment in this model, pulmonary injury is not worsened. In addition to reductions in circulating endotoxin levels, we have now shown that rG-CSF pretreatment reduces circulating tumor necrosis factor TNF) levels as well. It is not clear whether this is a direct effect related to rG-CSF, or whether rG-CSF modulated increases in host defense improve bacterial or bacterial toxin clearance. In order to determine whether rG-CSF pretreatment improves the clearance of microbial toxins directly. we have performed additional studies and evaluated the effects of rG-CSF pretreatment in animals challenged with endotoxin alone. In these studies we have shown that r-G-CSF pretreatment does in fact accelerate endotoxin clearance, and this accelerated clearance appears associated with improvements in cardiovascular function. To explore the nature of this accelerated clearance, we are not performing studies evaluating the effects of monoclonal antibodies directed against potential endotoxin receptors present on the neutrophil. We are initially studying the effects of MAb's directed against leukocyte adhesion molecule cD18.